Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors.
DNA-dependent activator of IFN regulatory factors (IRF; DAI, also known as ZBP1 or DLM-1) is a cytosolic DNA sensor that initiates IRF3 and NF-kappaB pathways leading to activation of type I IFNs (IFNalpha, IFNbeta) and other cytokines. In this study, induction of NF-kappaB is shown to depend on the adaptor receptor-interacting protein kinase (RIP)1, acting via a RIP homotypic interaction motif (RHIM)-dependent interaction with DAI. DAI binds to and colocalizes with endogenous RIP1 at characteristic cytoplasmic granules. Suppression of RIP1 expression by RNAi abrogates NF-kappaB activation as well as IFNbeta induction by immunostimulatory DNA. DAI also interacts with RIP3 and this interaction potentiates DAI-mediated activation of NF-kappaB, implicating RIP3 in regulating this RHIM-dependent pathway. The role of DAI in activation of NF-kappaB in response to immunostimulatory DNA appears to be analogous to sensing of dsRNA by TLR3 in that both pathways involve RHIM-dependent signaling that is mediated via RIP1, reinforcing a central role for this adaptor in innate sensing of intracellular microbes.
Kaiser
William J
WJ
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Upton
Jason W
JW
Mocarski
Edward S
ES
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000502:physiology; D020816:Amino Acid Motifs / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D025941:Protein Interaction Mapping; D016601:RNA-Binding Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; D016601:RNA-Binding Proteins; C485731:ZBP1 protein, human; D004247:DNA; D053422:Receptor-Interacting Protein Serine-Threonine Kinases